Retinal ganglion cell analysis in patients with sellar and suprasellar tumors with sagittal bending of the optic nerve

The study investigated clinical features of sellar and suprasellar tumors with optic nerve bending. Twenty-five patients (13 men/12 women; age, 59.0 ± 12.9 years) with optic nerve bending in one eye who underwent tumor resection for sellar and suprasellar tumors were included. The other eye, without optic nerve bending, was the control. The pre- and postoperative best-corrected visual acuity (BCVA) and ganglion cell layer (GCL) + inner plexiform layer (IPL) thickness were studied retrospectively using optical coherence tomography. Preoperative BCVA in the eye with optic nerve bending was significantly poor and improved significantly after tumor resection. Eyes with optic nerve bending had significantly less GCL + IPL thickness on the temporal side than eyes without optic nerve bending. Preoperative GCL + IPL thickness of the entire macula was reduced in eyes with optic nerve bending and poor postoperative BCVA compared to those with good postoperative BCVA. There was no significant difference in GCL + IPL thickness of eyes with optic nerve bending before and after tumor resection. Optic nerve bending caused by sellar and suprasellar tumors resulted in visual impairment and decreased retinal ganglion cells. Eyes with optic nerve bending and severely reduced GCL + IPL thickness may have less BCVA improvement after tumor resection.

www.nature.com/scientificreports/ with the sellar and suprasellar tumors included 13 men (52.0%) and 12 women (48.0%). Their average age was 59.0 ± 12.9 years. The mean optic nerve-canal bending angles (ONCBAs) were 56.7 ± 11.0° in bending eyes and 27.2 ± 8.4° in non-bending eyes (p < 0.001). Tables 2 and 3 show ONCBA and ophthalmologic parameters of all patients. Preoperative and postoperative best-corrected visual acuities (BCVAs) (logMAR) were 0.27 ± 0.33 and − 0.03 ± 0.12 and 0.03 ± 0.23 and − 0.06 ± 0.05 in bending and non-bending eyes, respectively (Fig. 2a). Preoperative BCVA of the bending eyes was significantly lower than that of the non-bending eyes (p < 0.001). Post- The enlarged sellar and suprasellar tumor causes visual field defects due to optic chiasm compression. However, sellar and suprasellar tumors, with or without optic chiasm compression, sometimes bend the optic nerve at the optic canal's entrance, leading to visual impairment. Table 1. Systemic characteristics of patients with sellar and suprasellar tumors. ONCBA optic nerve-canal bending angle.
Assessment of GCL + IPL using OCT. The preoperative GCL + IPL thicknesses in bending and nonbending eyes were 65.6 ± 12.8 µm and 71.4 ± 9.7 µm in the superior sector, 64.8 ± 13.1 µm and 68.8 ± 11.1 µm in the superior nasal sector, 61.9 ± 12.4 µm and 64.8 ± 10.6 µm in the inferior nasal sector, 63.8 ± 12.9 µm and 70.0 ± 8.4 µm in the inferior sector, 72.9 ± 12.8 µm and 80.6 ± 11.5 µm in the inferior temporal sector, and 69.9 ± 11.8 µm and 75.8 ± 8.0 µm in the superior temporal sector, respectively. The postoperative GCL + IPL thicknesses in the bending and non-bending eyes were 65.2 ± 12.7 µm and 71.0 ± 9.1 µm in the superior sector, 63.6 ± 13.7 µm and 68.2 ± 10.7 µm in the superior nasal sector, 60.8 ± 12.6 µm and 64.6 ± 10.5 µm in the inferior nasal sector, 64.6 ± 11.4 µm and 68.4 ± 8.2 µm in the inferior sector, 72.3 ± 12.7 µm and 79.9 ± 12.3 µm in the inferior temporal sector, and 69.1 ± 12.4 µm and 75.6 ± 8.0 µm in the superior temporal sector, respectively ( Fig. 3a-f). There was no significant difference in GCL + IPL thickness before and after surgery in all sectors (all p > 0.05). In both bending and non-bending eyes, the GCL + IPL thickness was lesser in the nasal sectors than in the temporal sectors, both before and after surgery. Notably, the GCL + IPL thickness in the superior temporal and inferior temporal sectors was significantly lesser in the bending eyes than in the non-bending eyes, both before and after surgery (p < 0.05) (Fig. 3e,f).
In bending eyes, we defined 19 eyes with postoperative BCVA (logMAR) of 0 or better as good visual outcome and 6 eyes with postoperative BCVA (logMAR) of less than 0 as poor visual outcome. The preoperative GCL + IPL thicknesses in the good visual outcome eyes and the poor visual outcome eyes were 69.9 ± 8.1 µm and 52.0 ± 15.3 µm in the superior sector, 68.7 ± 10.5 µm and 52.3 ± 12.8 µm in the superior nasal sector, 65.7 ± 9.6 µm and 49.8 ± 12.5 µm in the inferior nasal sector, 68.9 ± 6.6 µm and 47.8 ± 14.6 µm in the inferior sector, 76.9 ± 6.7 µm and 60.0 ± 17.9 µm in the inferior temporal sector, and 73.6 ± 6.7 µm and 58.2 ± 16.0 µm in Table 2. Angle of bending and ophthalmologic parameters of patients with optic nerve bending. ONCBA optic nerve-canal bending angle, BCVA best-corrected visual acuity(logMAR). www.nature.com/scientificreports/ the superior temporal sector, respectively (Fig. 4). The preoperative GCL + IPL thickness in eyes with poor visual outcome was significantly lesser than that in eyes with good visual outcomes in all sectors (p < 0.001, inferior sector; p < 0.01, other 5 sectors). Representative images of a patient with pituitary adenoma with optic nerve bending with good and poor visual outcomes are shown in Figs. 5 and 6.

Discussion
We retrospectively investigated the clinical features, including retinal ganglion cells (RGCs) analysis, of sellar and suprasellar tumors with sagittal bending of the optic nerve and compared them with those of non-bending optic nerve controls. Eyes with optic nerve bending due to sellar and suprasellar tumors had worse visual acuity and reduced GCL + IPL thickness in the temporal sectors, as measured by OCT, than eyes without optic nerve bending. In addition, eyes with optic nerve bending showed rapid improvement in visual acuity after tumor resection. Furthermore, in six eyes with poor visual outcome, the preoperative GCL + IPL thickness was significantly lesser than that in 19 eyes with good visual outcome. Yamaguchi et al. measured the sagittal angle of the optic nerve at the entrance of the optic canal using MR imaging in patients with sellar and suprasellar tumors and reported a new concept that sellar and suprasellar tumors cause not only optic chiasm compression but also optic nerve bending, resulting in visual impairment 4 . ONCBA basically affects ipsilateral vision 4 . Moreover, ipsilateral ONCBA is anatomically unrelated to contralateral visual dysfunction. However, when the ONCBA is large, the tumor is often large; therefore, the visual field defect due to chiasma compression may occur bilaterally. In addition, if the tumor is larger, the ONCBA on the contralateral side may be large. In this study, eyes with optic nerve bending had preoperative visual impairment, whereas eyes without optic nerve bending had good preoperative visual acuity (Fig. 2a). The mechanism of visual impairment due to optic nerve bending caused by sellar and suprasellar tumors remains unknown. The optic nerve at the entrance of the optic canal receives blood flow mainly from the superior pituitary artery, with little blood flow from the ophthalmic artery, which is prone to ischemia. The optic chiasm is rich in blood flow, supplied by branches from the internal carotid artery, anterior cerebral artery, and anterior communicating artery 6,7 . Hence, the optic nerve bending may be more likely to cause visual impairment due to ischemia than optic chiasm compression because the optic nerve at the optic canal's entrance has less blood flow than the optic chiasm.
The nasal GCL + IPL thickness is reduced in pituitary adenomas compared to normal subjects because tumorinduced optic chiasm compression damages the crossed fibers and retrogradely damages retinal ganglion cells 8 . In the current study, the GCL + IPL thickness was also lesser in the nasal sectors of sellar and suprasellar tumors www.nature.com/scientificreports/ with and without optic nerve bending. Notably, the GCL + IPL thickness in the temporal sectors was significantly lesser in bending eyes than in non-bending eyes. (Fig. 3e,f). Tumor-induced optic nerve bending at the entrance of the optic canal causes compression of the bony margin of the optic canal and stretching of the local optic nerve. Local compression of the optic nerve by bending in the narrow space of the optic canal's entrance may cause more dysfunction of the entire optic nerve cord than local compression in the relatively wide space of the optic chiasm, which may affect not only the nasal GCL + IPL but also the temporal GCL + IPL. Transsphenoidal surgery is an effective and safe treatment for most patients with pituitary adenomas and is expected to improve visual function 9 . Eyes with sellar and suprasellar tumors with optic nerve bending had severe visual impairment, but visual acuity improved with tumor resection (Fig. 2a). In contrast, eyes with optic nerve bending that showed little improvement in postoperative BCVA showed a significant decrease in preoperative GCL + IPL thickness (Fig. 4). Several factors have been previously investigated to predict visual recovery after optic chiasm decompression surgery. Retinal nerve fiber layer (RNFL) thinning, which reflects the loss of ganglion cell axons, is a predictor of poor visual recovery after surgery due to the optic chiasm compression and permanent denervation of the optic radiations and visual cortex [10][11][12] . Previous reports have shown that eyes with a normal RNFL have improved visual fields postoperatively compared to eyes with a thin RNFL 13 . In a representative case of good visual outcome group (case 1), the preoperative OCT of the optic nerve bending eye showed only a mild decrease in GCL + IPL in the predominantly superior nasal sector, and the postoperative BCVA improved (Fig. 5). In contrast, in a representative case of poor visual outcome group (case 2), preoperative OCT of the optic nerve bending eye revealed severe GCL + IPL reduction in all sectors, and postoperative BCVA did not improve (Fig. 6). Based on this result, the preoperative GCL + IPL thickness measured by OCT may predict the prognosis of postoperative visual function in sellar and suprasellar tumors with optic nerve bending. Furthermore, retinal ganglion cell death may progress faster with optic nerve bending than with optic chiasm compression. Prolonged visual symptoms in pituitary adenomas have been reported to decrease the improvement in visual function after tumor resection 13 . In optic chiasm compression and optic nerve bending, the optic nerve compression period may be associated with a decrease in RGCs. This study did not examine the time between the onset of visual impairment and ophthalmologic evaluation. The duration since optic nerve bending onset may affect visual impairment; hence, further studies are needed in the future. A previous report indicated that measuring RGCs may identify nerve fiber damage before RNFL in homonymous hemianopia 14 . Although not examined in this study, sellar and suprasellar tumors with optic nerve bending may also show changes in RNFL following RGCs. The limitations of our study include its retrospective nature, single-center design, and small sample size. Further research needs to include a large multi-center study.
In conclusion, sellar and suprasellar tumors with optic nerve bending cause thinning of the RGCs on the nasal and temporal sides. Eyes with optic nerve bending and severe retinal ganglion cell thinning had poor visual acuity even after tumor resection, and preoperative GCL + IPL thickness may be a prognostic factor for postoperative visual acuity.  www.nature.com/scientificreports/ on MR images before tumor resection, as previously reported 4 . Briefly, the ONCBA is the angle obtained by neurosurgeons measuring the extent of this bending on sagittal MR images formed by the optic nerve in the optic canal and the optic nerve in the intracranial subarachnoid space at the entrance of the optic canal. Each neurosurgeon specializing in pituitary tumor MR reading and surgery (R.Y. and M.T.) made evaluations, and any disagreements regarding conclusions were resolved by consensus. Optic nerve bending (large ONCBA) was defined as ONCBA ≥ 45°, and non-optic nerve bending (moderate ONCBA) was defined as ONCBA < 45°, as previously reported 4 . The exclusion criteria were as follows: (1) patients with a history of glaucoma or evident glaucomatous optic neuropathy; (2) high myopia (refractive error less than − 6 diopters); (3) retinal diseases, including epiretinal membrane and macular edema; (4) severe cataract, and (5) unclear optic nerve on MR imaging. All patients underwent ophthalmologic examinations, including best-corrected visual acuity (BCVA), intraocular pressure assessment, refraction, slit-lamp biomicroscopy, fundus examination, and GCL + IPL thickness measurement, using Cirrus high definition-OCT (Carl Zeiss Meditec, Dublin, CA, USA) in both the optic nerve bending and non-bending eyes before and 1 month after tumor resection (Fig. 7). BCVA was recorded as the decimal visual acuity and converted to logarithm of the minimum angle of resolution (logMAR) notation. The Cirrus HD-OCT ganglion cell analysis (GCA) algorithm automatically segmented the macula into superior, superior nasal, inferior nasal, inferior, inferior temporal, and superior temporal sectors, and measured the GCL + IPL thickness 5 .

Statistical analyses.
Data are presented as the mean ± standard deviation. An unpaired t-test was conducted to compare BCVA and GCL + IPL thickness measurements between the bending and non-bending eyes. The paired t-test was conducted to compare changes in BCVA and GCL + IPL thickness before and 1 month after surgery. The correction between BCVA and ONCBA was examined using Spearman's correlation coefficient. Statistical significance was set at p < 0.05. Statistical analyses were performed using GraphPad Prism version 6 (GraphPad Software Inc., La Jolla, CA, USA). www.nature.com/scientificreports/

Data availability
All data generated or analyzed during this study are included in this published article.